Two distinct prions in fatal familial insomnia and its sporadic form
Two distinct prions in fatal familial insomnia and its sporadic form
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DOI：
10.1093/braincomms/fcz045
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发表时间：
2019-01-01
影响因子：
4.8
通讯作者：
Kitamoto, Tetsuyuki
中科院分区：
文献类型：
--
作者：
Takeuchi, Atsuko;Mohri, Shirou;Kitamoto, Tetsuyuki
致死性家族性失眠症是一种遗传性朊病毒病，与朊病毒蛋白基因第178位密码子天冬氨酸被天冬酰胺取代有关。虽然标志性的病理特征是丘脑和橄榄核变性，有一个病人与一个非典型的致命的家族性失眠症没有标志性的功能。病理变异性的原因尚不清楚。我们分析了日本致命的家族性失眠症的亲属，并比较了一个非典型的临床病理致命的家族性失眠症表型的情况下，典型的致命的家族性失眠症表型的情况下，使用多行基因敲入小鼠和蛋白质错误折叠循环扩增的传输研究。我们还分析了散发性致命性失眠症的遗传性和放大特性。传播研究表明，典型的致命性家族性失眠症与丘脑和橄榄变性显示成功的传播，只有使用敲入小鼠表达人-鼠嵌合朊蛋白基因。非典型致死性家族性失眠症伴海绵状改变，仅用表达库田鼠朊蛋白基因的敲入小鼠才能成功传播。两个散发性致死性失眠病例与丘脑和橄榄核变性表现出相同的遗传性作为典型的致死性家族性失眠表型。有趣的是，一例伴有丘脑/橄榄核变性和海绵状变化的散发性致死性失眠病例显示了典型和非典型致死性家族性失眠表型的遗传性。蛋白质错误折叠循环扩增可以扩增典型的致死性家族性失眠症病例和散发性致死性失眠症病例，但不能扩增非典型致死性家族性失眠症表型或其他散发性克雅氏病亚型。除了临床表现和神经病理学特征，典型和非典型致死性家族性失眠表型之间的传输特性和放大特性是不同的。这表明，两种不同的朊病毒与致死性家族性失眠表型的多样性，这两种朊病毒也可以检测到散发性致死性失眠。
Fatal familial insomnia is a genetic prion disease, which is associated with the aspartic acid to asparagine substitution at codon 178 of the prion protein gene. Although the hallmark pathological feature is thalamic and olivary degeneration, there is a patient with an atypical fatal familial insomnia without the hallmark feature. The cause of the pathological variability is unclear. We analysed a Japanese fatal familial insomnia kindred and compared one atypical clinicopathological fatal familial insomnia phenotype case and typical fatal familial insomnia phenotype cases with transmission studies using multiple lines of knock-in mice and with protein misfolding cyclic amplification. We also analysed the transmissibility and the amplification properties of sporadic fatal insomnia. Transmission studies revealed that the typical fatal familial insomnia with thalamic and olivary degeneration showed successful transmission only using knock-in mice expressing human-mouse chimeric prion protein gene. The atypical fatal familial insomnia with spongiform changes showed successful transmission only using knock-in mice expressing bank vole prion protein gene. Two sporadic fatal insomnia cases with thalamic and olivary degeneration showed the same transmissibility as the typical fatal familial insomnia phenotype. Interestingly, one sporadic fatal insomnia case with thalamic/olivary degeneration and spongiform changes showed transmissibility of both the typical and atypical fatal familial insomnia phenotypes. Protein misfolding cyclic amplification could amplify both typical fatal familial insomnia cases and sporadic fatal insomnia cases but not the atypical fatal familial insomnia phenotype or other sporadic Creutzfeldt-Jakob disease subtypes. In addition to clinical findings and neuropathological features, the transmission properties and the amplification properties were different between the typical and atypical fatal familial insomnia phenotypes. It is suggested that two distinct prions were associated with the diversity in the fatal familial insomnia phenotype, and these two prions could also be detected in sporadic fatal insomnia.